Artificial bone forming method by powder lamination method

ABSTRACT

An artificial bone forming method, comprising a) a powder layer forming step ( 32 ) for forming, into a flat powder layer ( 6 ), a powder bone material ( 5 ) having biocompatibility and hardening by hydration, b) a partial hardening step ( 34 ) for jetting an aqueous solution ( 7 ) with biocompatibility to a part of the powder layer to harden a jetted portion ( 6   a ) by hydration, and c) an artificial bone forming step ( 36 ) for repeating the steps a) and b) for lamination to form a specified artificial bone ( 9 ) of a predetermined three-dimensional structure in which the hardened portions ( 6   a ) are connected to each other.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to an artificial bone forming method by apowder lamination method.

2. Description of the Related Art

Rapid prototyping is called a lamination forming method which laminatesa sectional shape of an object to create a three-dimensional object. Alamination method (powder fixing method) which is a kind of rapidprototyping and uses powder as materials is disclosed or filed (notlaid-open) in each of Nonpatent Documents 1, 2 and Patent Documents 1 to5.

Further, means for artificially forming eyeballs, teeth, bones and thelike which constitute a living organism by using the powder laminationmethod are disclosed or filed (not laid-open) in Patent Documents 6 to9.

“Solid color copying and method” (not laid-open) of the Patent Document6 includes a sample section imaging step (A) of sequentially extruding asample in a predetermined direction to cut it, thereby imaging atwo-dimensional image of a cut section, a data processing step (B) ofcalculating a three-dimensional internal structure of the sample fromthe two-dimensional image to convert it into data which can be subjectedto color rapid prototyping, and a solid color model building step (C) ofbuilding a solid color model by using a color rapid prototyping device.

“Mass production of dental restoration by solid free-form fabricationmethods” of the Patent Document 7 includes (a) forming a layer of aceramic or composite material, (b) adding a binder to the layer, (c)repeating (a) and (b) many times to form a number of interconnectedlayers into a shape of a tooth prosthesis, and (d) reinforcing theformed material to fabricate a tooth prosthesis.

“Mass production of shells and models for dental restoration produced bysolid free-form fabrication methods” of the Patent Document 8 includes(a) preparing a shell shape of a tooth prosthesis by using digital data,(b) forming a layer of a polymer material, and (c) repeating (b) manytimes to form a number of interconnected layers into a shell shape basedon the digital data.

“Artificial bone forming method” of the Patent Document 9 includes (a) astep for transporting a powder material for a living organism and aliquid material through different flow paths to the vicinity of a nozzletip of a jetting device, (b) a step for jetting a mixture of the livingorganism powder material and the liquid material from a nozzle of thejetting device to a solid surface, and depositing the mixture of theliving organism powder material and the liquid material on the solidsurface to form a layer, and (c) a step for further jetting the mixtureof the living organism powder material and the liquid material to thelayer to repeat lamination of deposition surfaces of the mixture,thereby stacking a plurality of layers to form a bone three-dimensionalstructure into a solid shape.

Nonpatent Document 1: pp. 63 to 65,“Fabrication of multicolor model bycolor RP machine” by Yamazawa, Anzai and et al., 19th Rapid PrototypingSymposium, 2000

Nonpatent Document 2: “Substantiation of molecular structure bylamination forming method” by Yamazawa, Anzai and et al.

Patent Document 1: Three-dimensional printing techniques”, specificationof U.S. Pat. No. 5,204,055

Patent Document 2: “Method of three dimensional printing”, specificationof U.S. Pat. No. 5,902,411

Patent Document 3: “Method and apparatus for prototyping a threedimensional object”, specification of U.S. Pat. No. 6,375,874

Patent Document 4: “Three-dimensional shape forming method by powderlamination method”, JP A 9-324203

Patent Document 5: “Lamination forming method of functional material”not laid-open, specification of JP A 2002-205825

Patent Document 6: “Solid color copying method and device” notlaid-open, specification of JP A 2002-226859

Patent Document 7: “Mass production of dental restoration by solidfree-form fabrication methods”, specification of U.S. Pat. No. 6,322,728

Patent Document 8: “Mass production of shells and models for dentalrestoration produced by solid free-form fabrication methods”,specification of U.S. Pat. No. 20020064745

Patent Document 9: “Artificial bone forming method” not laid-open,specification of JP A 2002-377836

Conventionally, an artificial bone has been made of a metallic materialsuch as stainless or titanium alloy, abrasion-resistant plastic, or thelike, and used for a bone replacement technology. Such an artificialbone acts for a dysfunctional joint. However, the metallic material orthe abrasion-resistant plastic has had a problem that long-time use isimpossible because of a change with time such as abrasion, corrosion orswelling.

Recently, on the other hand, it has been made possible to form anartificial bone similar in shape to a target bone by putting ceramics ina mold to burn it or shaving it off from a burned block. In the case ofsuch an artificial bone, however, its appearance structure alone issimilar, and there remains a problem regarding biocompatibility orabsorption substitution while no change with time such as abrasion,corrosion, or swelling occurs.

SUMMARY OF THE INVENTION

The present invention has been developed to solve the aforementionedproblems. That is, it is an object of the present invention to providean artificial bone forming method which can form an artificial bonehaving a shape similar to that of a target bone, and a nature andcomponents similar to those of a bone of a living organism, andimplantable in substitution technology.

According to the present invention, there is provided an artificial boneforming method by a powder lamination method, comprising a) a powderlayer forming step for forming, a powder bone material havingbiocompatibility and hardening by hydration, into a flat powder layer,b) a partial hardening step for jetting an aqueous solution withbiocompatibility to a part of the powder layer to harden a jettedportion by hydration, and c) an artificial bone forming step forrepeating the steps a) and b) for lamination to form a specifiedartificial bone of a predetermined three-dimensional structure in whichthe hardened portions are connected to each other.

According to a preferable embodiment of the present invention, thepowder bone material is constituted of an inorganic component such ascalcium phosphate and other bone components, and the aqueous solution isa liquid mixture or a suspension of water and a water-soluble biopolymerwhich is a component derived from a living organism.

The powder bone material is a calcium salt such as calcium phosphate,hydroxyapatite, human bone, animal bone, alumina, collagen, polylacticacid, a copolymer of polylactic acid and polyglycolic acid, or a mixturethereof.

Furthermore, the aqueous solution is a liquid mixture or a suspension ofwater and soluble collagen, proteoglucan, linkprotein, sodium tartrate,a pH adjuster, a bone growth factor, fibrin, PRP (Platelet-Rich Plasma),a polysaccharide, an amino acid polymer, polylactic acid, a copolymer ofpolylactic acid and polyglycolic acid, or a mixture thereof.

Furthermore, two or more kinds of liquid mixtures which react with eachother in a liquid layer to bring about a hardening reaction are put inseparate vessels, and they are jetted through a plurality of ink jetnozzles so as to be mixed and hardened at a jetting portion.

Furthermore, a component which further promotes a crosslinking reactionor polymerization of a polymeric component of the artificial bone is putin a vessel different from a vessel for a living material to be reactedor polymerized, and the component is jetted through another ink jetnozzle to be mixed at an intended position.

For example, a mixture of an ethylene silicate solution and a catalystis jetted through two different nozzles to hydrolyze ethylene silicatein the state of a hydroxyapatite powder layer, thereby preparing andhardening a polymer of the silicate.

Furthermore, it is desirable that after the step c), the methodcomprises d) an artificial bone reinforcing step for discharging a gascontained in the artificial bone to further reinforce the hardenedportions by a reaction by using a change in pressure. Since a suspensionof collagen or polylactic acid has a high viscosity, its penetration bycapillary phenomenon is difficult. In consequence, to positivelyaccelerate the penetration of the suspension into a bone structure, itis desirable that a reduced pressure treatment or a pressure treatmentis carried out to promote the replacement of air therein with thesolution to be hardened.

Furthermore, after the artificial bone reinforcing step or the step c),a hardening reaction is promoted for the formed artificial bone directlyunder high-temperature and high-pressure water vapor or under a dry hightemperature in an autoclave.

Furthermore, it is preferable to carry out a high-temperature heattreatment in a vacuum state or an oxygen-free atmosphere to induce areaction between biopolymers of an artificial bone formed by mixing thebiopolymers, a reaction with other components, or melting.

The strength of the collagen increases by drying the collagen andtreating it in an atmosphere of 120 to 130° C. to polymerize it.Moreover, the strength and impact strength of polylactic acid in thebone structure increase by heating it at a melting point of thepolylactic acid or more to melt inorganic bone components and to bondparticles.

Furthermore, according to the present invention, there is provided anartificial bone forming method by a powder lamination method, comprisinga) a two-dimensional data creating step for sequentially moving a targetbone in a predetermined direction to create two-dimensional data of acut section, b) a tissue data processing step for creating data to besubjected to rapid prototyping for a plurality of tissues constituting abone from the two-dimensional data, and c) an artificial bone formingstep for forming an artificial bone constituted of a plurality of tissuestructures by using a rapid prototyping device.

The tissue data is constituted of a plurality of data selected from acancellous bone, a bone trabecula, a lumen, and a cortical bone.

According to the method of the present invention, the bone materialhaving biocompatibility and the aqueous solution alone are used. Hence,it is possible to form an artificial bone having a nature and componentssimilar to those of a bone of a living organism, and implantable insubstitution technology.

The artificial bone reinforcing step is taken, and the hardeningreaction is promoted in the autoclave or the heating chamber whennecessary. Hence, it is possible to provide strength equal to that of abone of a living organism, and to leave the artificial bone in theliving organism for a long time.

Furthermore, based on the target bone, the data constituted of theplurality of data selected from the cancellous bone, the bone trabecula,the lumen, and the cortical bone, and subjected to rapid prototyping iscreated, and the artificial bone having the plurality of organizationstructures is formed by using the rapid prototyping device. Hence, it ispossible to form an artificial bone having a shape similar to that of atarget bone, and a similar internal structure.

Other objects and advantageous features of the present invention willbecome apparent upon reading of the following detailed description madewith reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram showing a structure of a bone;

FIGS. 2A to 2D are diagrams showing sectional structures of bones;

FIG. 3 is a diagram showing a flow of data by an artificial bone formingmethod of the present invention;

FIG. 4 is a diagram showing a powder lamination process by theartificial bone forming method of the present invention; and

FIG. 5 is a block diagram of an ink jet head compatible to the structureof the bone.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The preferred embodiment of the present invention will be describedbelow with reference to the accompanying drawings. Throughout thedrawings, similar portions are denoted by similar reference numerals,and repeated explanation will be avoided.

FIG. 1 is a schematic diagram showing a structure of a bone. As shown,even if it were animal or human bones, bones are generally classifiedinto a proximal epiphysis, a distal epiphysis, and a diaphysistherebetween which constitute a joint. The epiphysis is constituted of ajoint cartilage, a compact bone, a spongin, and an epiphysial line froma surface. The diaphysis is constituted of a periosteal, a compact bone,a yellow bone marrow, and the like from a surface.

FIGS. 2A to 2D are images showing sectional structures of bones. In thedrawings, FIG. 2A is an entire image showing a thighbone, a cancellousbone, a cortical bone, and a lumen, FIG. 2B shows a cortical bone, FIG.2C shows a thighbone cancellous bone, and FIG. 2D shows a skeletal lineand a trabecular thickness.

It can be understood from FIGS. 1 and 2A to 2D that the bone is nothomogeneous as a whole, and constituted of a plurality of tissues(cancellous bone, trabecula, lumen, cortical bone, and the like).

FIG. 3 shows a flow of data by an artificial bone forming method of thepresent invention. In the drawing, the artificial bone forming method ofthe invention includes a two-dimensional data creating step 10, a tissuedata processing step 20, and an artificial bone forming step 30.

In the two-dimensional data creating step 10, a target bone (animal orhuman bone) is sequentially moved in a predetermined direction to createtwo-dimensional data 2 of a cut section. In this step, the bone may becut by actually using a cutter, or data may be nondestructively obtainedby CT scanning or the like. The obtained two-dimensional data 2 will bereferred to as CT data in this example.

In the tissue data processing step 20, data 4 to be subjected to rapidprototyping for a plurality of tissues constituting a bone is createdfrom the two-dimensional data 2. In this example, an STL file 3 isformed for each tissue from the CT data 2, and then tissue data 4(cancellous bone data, trabecula data, lumen data, and cortical bonedata) classified into a cancellous bone, a trabecula, a lumen, and acortical bone is created from each slice data (CT data 2).

In the artificial bone forming step 30, an artificial bone 9 constitutedof a plurality of tissue structures is formed by using a rapidprototyping device.

FIG. 4 shows a powder lamination process by the artificial bone formingmethod of the present invention. This powder lamination processcorresponds to the artificial bone forming step 30.

The powder lamination process includes a powder layer forming step 32, apartial hardening step 34, and an artificial bone forming step 36.

In the powder layer forming step 32, a powder bone material 5 havingbiocompatibility and hardening by hydration is formed into a flat powderlayer 6.

In the partial hardening step 34, an aqueous solution 7 (hardeningliquid) having biocompatibility is jetted to a part of the powder layer6 to harden a jetted portion 6 a by hydration.

In the artificial bone forming step 36, the powder layer forming step 32and the partial hardening step 34 are repeated for lamination to form anartificial bone 9 having a desired three-dimensional structure in whichthe hardened portions 6 a are connected to each other.

Further, according to the method of the invention, in an artificial bonereinforcing step (not shown), the artificial bone 9 formed in theartificial bone forming step 36 is held under reduced pressure, a gascontained therein is discharged, and the hardened portion is reinforcedmore by hydration. Preferably, after the artificial bone reinforcingstep, a hardening reaction of the formed artificial bone is promotedunder high-temperature and high-pressure water vapor in an autoclave.

FIG. 5 is a block diagram of an ink jet head compatible to a bonestructure. This ink jet head 8 is constructed in such a manner that aplurality of nozzles are serially arranged in a direction orthogonal toa scanning direction (X), and a jetting amount of a hardening liquid(aqueous solution 7) corresponding to a lumen, a trabecula, a cancellousbone, and a cortical bone is changed to control a fixed portion and itshardness.

Two or more kinds of liquid mixtures which react with each other in aliquid layer to bring about a hardening reaction are preferably put inseparate vessels, and jetted from the plurality of ink jet nozzles 8 tobe mixed and hardened at a jetting portion. Further, a component whichpromotes a crosslinking reaction or polymerization of a polymericcomponent of the artificial bone is put in a vessel different from thatof a living material to be reacted or polymerized, jetted from adifferent ink jet nozzle to be mixed at an intended position.

In a bone tissue of a living organism, a hard inorganic substrate madeof a hydroxyapatite (phosphorus hydroxide ashstone) crystal, andchondroitin sulfate (sulfate-coupled type proteoglycan) are buried in acollagen I type to form a matrix. For cells, there are an osteoblast anda bone cell. The former actively produces organic bone substrates, andlimes are deposited thereon to form lamellar inorganic substrates. Thebone cell is a cell in which the osteoblast is buried in a bonesubstrate made by itself to lose its bone substrate forming function,and the cell is located in a minimum cavity. As another kind of cell,there is a multinucleated osteoclast, which causes bone substratemelting. As in the case of a cartilage tissue, the bone tissue iscovered with a periosteal which is a connective tissue, and stronglyconnected to another bone tissue by Sharpie fiber (type-I collagen).

According to the present invention, a special bioactive artificial bonematerial (powder bone material 5) which reacts with water to be hardenedis used to form the artificial bone 9 in three-dimensional laminationwithout using a burning process. Reactive components are separatelyjetted for the purpose of improving biocompatibility, absorptionsubstitution for a living organism, and strength to form the bone,whereby an artificial bone having a function, components and a shapesimilar to those of a bone of a living organism, impossible to beobtained by a normal reaction method, can be formed.

According to a feature of the forming method, as a bone internalstructure (trabecula, cancellous bone) can be reproduced,biocompatibility is high not only for components but also for astructure, and substitution for the bone of the living organism is fast.

Furthermore, by burying the bone cell in a porous portion of the boneinternal structure, it is possible to apply the artificial bone as acell support (scaffold) for medical osteoclassis.

Hereinafter, the present invention will be described more in detail.

1) By the present invention, two-dimensional data obtained from a CTimage of X-ray, MRI or the like is subjected to CAD conversion, and anartificial bone for implantation is formed by a three-dimensionallamination forming device in a CAM process. This forming method mustsatisfy some conditions.

a) For a particle size of a powder (powder bone material 5) of a powderlayer 6, an average particle diameter is preferably 10 microns or lessfrom the standpoint of forming strength and hardening reaction time.Hardening time is faster as a particle is smaller, and strength afterhardening tends to increase. However, as crushing into particles of lessthan 100 nanometers is extremely difficult, an average particle diameterof 100 nanometers or more is used.

When powders having two kinds of particle sizes in which medium valuesare apart from each other by three times as much as a particle sizedistribution to form an artificial bone, a filling density increases toreduce porosity. Accordingly, high physical strength is obtained.

b) A liquid phase (aqueous solution 7) to be jetted is mainlyconstituted of water soluble components. For example, an aqueoussolution of soluble collagen, a pluteogulycan, a link protein, sodiumtartrate and a buffer component for pH adjustment is prepared to havesuch a viscosity that the solution can be jetted through the ink jetnozzle.

c) A roller is generally used for flattening the powder layer. To form aflat surface, a particle size of a powder, a rotational speed of theroller, and a moving speed must be adjusted.

d) To increase strength of an artificial bone after a forming operation,it is necessary to assist a reaction between formed hardeningcomponents. During the forming operation, a gas is contained in theformed object, and a reaction between a powder phase and a liquid phaseby jetting may not be enough. Thus, a reaction must be completed byaddition after the forming.

Basically, an object is dipped in a liquid of the same component as thatof a jetted liquid layer or an artificial body liquid, and pressure(reduced pressure) is applied by a vacuum pump to remove a gas from theinside, thereby assisting infiltration of a liquid layer componenttherein.

2) For the powder layer 6, a water insoluble inorganic component havinghigh biocompatibility, especially a calcium compound such as calciumphosphate having a nature of being hardened by hydration, is preferable.Other water insoluble or hardly soluble components are mixed as fineparticles to form a powder bed used during jetting forming.

3) When the artificial bone 9 is formed by the jetted liquid 7 from theink jet nozzle 8, a jetted solution layer is made of a component forassisting polymerization, crosslinking, connection and the like with thewater soluble component of the bone of the living organism. Further, aspH at the time of hardening is important for the inorganic component, apH buffer material must be added.

A representative bone component of a living organism is collagen. Thereare known eighteen kinds of collagen types (collagen families). Eachtype has an organ idiosyncrasy. For example, I-type collagen is mainlypresent in a skin, a bone, a tendon, and the like, II-type collagen ismainly present in a cartilage, a corpus vitreum, and the like, II-typecollagen is mainly present in a blood, a skin, and the like, and IV-typecollagen is mainly present in a basilar membrane, and the like. Formingtargets of a bone and a cartilage are I and II type collagens.

The pluteogulycan as another bone component of the living organism is ageneric term of a molecule in which glycosaminoglycan is covalent bondedto a protein, and it is a main component of a cell surface andout-of-cell matrix. The glycosaminoglycan is classified, in accordancewith its skeleton structure, into chondroitin sulfate, deltaman sulfate,heparin sulfate, heparin, ketaran sulfate, and hyaluronic acid.

As another component, link protein is known to increase strength of thebone and the cartilage. Fibrin, platelet-rich blood serum (PRP), variouspolysaccharides, an amino-acid polymer, and the like can increase thestrength of the bone because of high biocompatibility.

The artificial bone can be formed by putting a bone cell growth factoror the like in the liquid phase for the purpose of quickeningsubstitution of the formed artificial bone material for a bone cell.Especially, a bone forming factor (BMP) has a strong bone reproductioninducing ability. As other cytokines to promote bone cell growth andsubstrate growth, there are a basic fibroblast growth factor (b-FGF), atransforming growth factor (TGFβ), an insulin growth factor (IGF-1), andthe like.

4) Aggregation or precipitation occurs when the liquid phase componentsfor bone formation are mixed, causing a reduction in forming performanceor a trouble in jetting from the nozzle. In this case, components whichreact with each other are stored in different vessels, and separatelyjetted from the circuit and the nozzle during formation to be mixed onthe target powder layer. The bone components of the living organismcoagulate and react with each other to from a matrix or a complex. Toreproduce such a complex component environment, a plurality of liquidphases must be physically separated, and a reaction thereof must bemechanically controlled to bring about a reaction at a target place.

5) To increase strength and tenacity of the formed artificial bone, itis useful to form a polymer by polymerization of biomolecules and ameshed structure by crosslinking. A polymerization agent or acrosslinking agent is put in the liquid phase jetted from the nozzle toimprove physical properties of the artificial bone after the formation,whereby an artificial bone similar to a bone of a living organism can beformed.

6) Hydration hardening reaction of the inorganic component of the formedartificial bone is promoted by high steam pressure at a hightemperature. The artificial bone is processed at a sterilizing cycle ina sterilization autoclave to greatly shorten hardening time.

Furthermore, reaction processing is executed in an atmosphere of ahigh-temperature dry state for a long time in a drying process of theautoclave to crosslink, and polymerize the biopolymers in the artificialbone to react with each other, thereby improving the strength and thetenacity more. Because of the process of a higher temperature and alonger time than a normal sterilization process, a sterile state of theartificial bone is simultaneously established.

EXAMPLE 1

For a powder layer of a three-dimensional lamination forming deviceequipped with a powder flattening roller, α-TCP calcium phosphate fineparticles were used, sodium tartrate, and a chondroitin sodium sulfateaqueous solution were used for an ink jet liquid layer, and a liquidlayer is jetted onto the powder after flattening into a thickness of 100microns by the roller to draw a two-dimensional image. This work wasrepeated to stack powder layers, thereby forming a solid object.

Unnecessary unhardened powders were removed from the formed object, theobject was dipped in the same aqueous solution as that of the ink jetliquid layer to additionally harden its inside, and pressure was reducedin a closed vessel by a vacuum pump.

After bubbles were removed from the formed object for substitution withthe liquid layer by the pressure reduction processing, the object wasleft still at about a room temperature for three days to finish ahardening reaction. As a result, an artificial bone 9 having a desiredthree-dimensional structure was formed.

EXAMPLE 2

Soluble 0.2% butacollagen is mixed with a solution containing sodiumtartrate and chondroitin sodium sulfate to produce a deposited object inan ink jet liquid phase by using the same device and the same powderlayer as those of the Example 1, and thus a collagen containedartificial bone was formed by jetting from a vessel and a nozzle of adifferent system. By this method, production of deposited objects wasprevented.

EXAMPLE 3

During forming by putting collagen and a hyaluronic acid in a liquidphase, a small amount of a glyoxal solution was jetted from a vessel anda nozzle of a different system to form an artificial bone. Then, curingof hydration hardening reaction and crosslinking reaction was carriedout, and the bone was left in agitation purified water for twenty fourhours to remove unreacted articles about three days later.

EXAMPLE 4

Using hydroxyapatite powders of an average particle diameter of 30microns for the same device as that of the Example 1, ethylsilicate anda catalyst solution (hardening agent) were jetted to the hydroxyapatitepowder layer at a weight ratio of 30:1 to be hardened. A complex ofhydroxyapatite and silica was formed, and the dry hardened object wasdipped in a hardening agent B (in post processing agent) fro about 30minutes to form a glass shiny object.

When 3-hour burning was executed again at about 800° C. after thedrying, a silica polymerization degree was increased to improvestrength.

EXAMPLE 5

As in the case of the Example 1, a lamination was formed by using mixedpowders in which calcium phosphate raw material powders and polyacticacid powders were mixed at a weight ratio of 70:30. After the formedobject was dried to remove water, 3-hour heating was carried out at 140°C. As a result, the melted polyactic acid worked as a binder betweencalcium phosphate particles to form an artificial bone having not onlyhigh compression strength but also high bending strength.

EXAMPLE 6

An artificial bone formed by the same method as that of the Example 2was put in a sterilization bag, put in an autoclave to remove air fromthe artificial bone formed object in an air removing step, andhigh-temperature and high-humidity processing was carried out at a 121°C. for about one hour (mainly promotion of hydration hardeningreaction). After removal of internal vapor, processing was carried outfor about 3 hours in a drying step of 130° C. (promotion of collagencrosslinking reaction).

For a cartilage matrix, aggrecan (cartilage puluteoglycan) of a largemolecular weight was connected to hyaluron, and linkprotein which isglycoprotein to 40 kd reinforced the connection of both to prepare aporous matrix made of gelatin and hydroxyapatite (HA). This matrix wasprepared by using a small amount of carbodiimide (EDCI) for acrosslinking agent, and dipping a water soluble sponge of gelatin and HAin 90% (w/v) acetone/water mixed solution. This sponge type biomaterialwas formed as a cover for a wound or a tissue engineering scaffold.

A complex of HA and collagen was prepared by coagulating two componentsin an aqueous acetic acid solution, and crosslinking them throughglyoxal or exess-rich acetic acid starch dialdehyde.

Another composition of HA and collagen was prepared by crosslinking adry HA/collagen coagulated object through polyethylene oxide andhexamehylene isocyanate.

A complex material of hydroxyapatite and collagen-HA was prepared byadding hydroxyapatite particles in an HA solution, and mixing them witha collagen fiber suspended in water. A final product constituted of acomposition of hydroxyapatite 90%, collagen 9.2%, and HA 0.8% (w/v) hasbiocompatibility and mechanical strength, and was used as a filler for abone loss.

There are materials having multiple and regularly arranged carboxylgroups. These are full glycodxamionoglycan, pectin, alginic acid,carboxyl methyl cellulose (CMC), and polyacrylic acid. When thesepolymers are blended with HA and crosslinking chemicals described beloware applied, a complex and new-dimensional hydrogel containing HA bychemical modification is obtained.

Properties of alginic acid gel formation (by chelated metal formation)promoted formation of a hydrogen when it was blended with HA.Accordingly, the alginic acid HA gel was prepared by diffusing calciumions in an alginic acid-HA mixture. A gel having an alginic acid and Haratio of 1:1 exhibited sufficient mechanical characteristics. Thiscomposition is applied for a joint surgical operation as a carrier of abiocompatible polymer and because it is stable in a bone liquid.

An HA containing copolymer has been prepared to optimize mechanicalstrength and to obtain conditions optimal for medicine delivery andstability in a living organism. For example, a comb-shaped polymeramphoteric electrolyte copolymer having poly(L-lysine) (PLL) as a mainchain, a connected part with a DNA, and an HA chain having a cellspecific ligand as a side chain was prepared by targeting a sinusoidalinner skin cell of the liver. An HA reduction end and a PLL ε-aminogroup were covalent-bonded by a reduction amino reaction using sodiumcyanoborohydride to obtain a comb-shaped copolymer (PLL-graft HA). Thispolycationic PLL skeleton was selectively connected with a polyanionicDNA even when the HA chain was present. Further, the PLL-graft-HA-DNAcomplex may have formed a multilayer structure whose outer side wassurrounded with hydrated HA free of hydrophobic PLL-DNA. The formationof the complex with free HA was considered essential for directing it toa target cell.

As described above, the present invention relates to the method oftargeting a defective bone part in orthopedic surgery, plastic surgery,neurosurgery or dental surgery, and custom-making an artificial bone forthe defective bone part in accordance with patient's wish.

In the industrial three-dimensional lamination forming method used forcreating a model or a mold, a material containing basic components of ahuman bone and a cartilage bone is used.

A water insoluble component is mainly used to form a powder layer forlamination, and a water soluble component is jetted through a nozzle tobe printed on the lamination powder surface.

An inorganic component such as calcium phosphate which reacts with wateror a biocomponent to be solidified, and other bone components are usedfor the powder layer. A soluble component derived from a bone isdissolved in an aqueous solution liquid phase of the ink jet, and jettedto the powder layer to form a three-dimensional shape, whereby animplantable artificial bone having components similar in nature to thoseof a bone of a living organism can be formed.

The preferred embodiments of the present invention have been described.However, it can be understood that these embodiments are in no waylimitative of a scope of claims of the invention. Conversely,improvements, modifications, equivalents and others are all included inthe scope of appended claims of the invention.

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 10. An artificialbone forming method by a powder lamination method, wherein theartificial bone forming method comprises: (a) a two-dimensional datacreating step including sequentially moving a target bone in apredetermined direction to create two-dimensional data of a cut section;(b) a tissue data processing step including creating data to besubjected to rapid prototyping for a plurality of tissues comprising abone from the two-dimensional data; and (c) an artificial bone formingstep including forming an artificial bone comprised of a plurality oftissue structures by using a rapid prototyping device.
 11. Theartificial bone forming method by the powder lamination method accordingto claim 10, wherein the tissue data is comprised of data correspondingto tissue selected from the group consisting of a cancellous bone, abone trabecula, a tissue provided with a lumen, and a cortical bone.